Sirolimus
(INN/USAN), also known as rapamycin, is an immunosuppressant
drug used to prevent rejection in organ transplantation;
it is especially useful in kidney transplants. A macrolide,
sirolimus was first discovered as a product of the bacterium
Streptomyces hygroscopicus in a soil sample from
Easter Island[1]
an island also known as "Rapa Nui", hence the name.[2]
It is marketed under the trade name Rapamune by Wyeth.
Sirolimus was originally developed as an antifungal agent.
However, this was abandoned when it was discovered that
it had potent immunosuppressive and antiproliferative properties.

Mechanism
of action

Unlike
the similarly-named tacrolimus, sirolimus is not a calcineurin
inhibitor. However, it has a similar suppressive effect
on the immune system. Sirolimus inhibits the response
to interleukin-2 (IL-2) and thereby blocks activation
of T- and B-cells. In contrast, tacrolimus inhibits the
production of IL-2.

The
mode of action of sirolimus is to bind the cytosolic protein
FK-binding protein 12 (FKBP12) in a manner similar
to tacrolimus. However, unlike the tacrolimus-FKBP12 complex
which inhibits calcineurin (PP2B), the sirolimus-FKBP12
complex inhibits the mammalian target of rapamycin
(mTOR) pathway by directly binding the mTOR Complex1 (mTORC1).
mTOR is also called FRAP (FKBP-rapamycin associated protein)
or RAFT (rapamycin and FKBP target). FRAP and RAFT are
actually more accurate names since they reflect the fact
that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin
complex can bind FRAP/RAFT/mTOR.

Use
in transplant

The
chief advantage sirolimus has over calcineurin inhibitors
is that it has low toxicity towards kidneys. Transplant
patients maintained on calcineurin inhibitors long-term
tend to develop impaired kidney function or even chronic
renal failure; this can be avoided by using sirolimus
instead. It is particularly advantageous in patients with
kidney transplants for hemolytic-uremic syndrome, as this
disease is likely to recur in the transplanted kidney
if a calcineurin-inhibitor is used. However, on October
7 2008, the FDA approved safety labeling revisions for
sirolimus to warn of the risk for decreased renal function
associated with its use.

Sirolimus
can also be used alone, or in conjunction with calcineurin
inhibitors and/or mycophenolate mofetil, so as to provide
steroid-free immunosuppression regimes. However, impaired
wound healing and thrombocytopenia is a possible side
effect of sirolimus; therefore, some transplant centres
prefer not to use it immediately after the transplant
operation, instead administering it only after a period
of weeks or months. Its optimal role in immunosuppression
has not yet been determined, and is the subject of a number
of ongoing clinical trials.

Lifespan
extension in mice

In
a 2009 study, the lifespans of mice fed rapamycin were
increased between 28-38% from the beginning of treatment,
or 9-14% in total increased maximum lifespan. Of particular
note, the treatment began in mice aged 20 months, the
equivalent of 60 human years. This suggests the possibility
of an effective anti-aging treatment for humans at an
already-advanced age, as opposed to requiring a lifelong
regimen beginning in youth.[3]
However, because it strongly suppresses the immune system,
the drug cannot be easily used by humans. While the mice
in the study were housed in pathogen-free facilities,
people taking rapamycin are very susceptible to life-threatening
infections, and require constant medical supervision.[4]

Anti-proliferative
effects

The
anti-proliferative effect of sirolimus has also been used
in conjunction with coronary stents to prevent restenosis
in coronary arteries following balloon angioplasty. The
sirolimus is formulated in a polymer coating that affords
controlled release through the healing period following
coronary intervention. Several large clinical studies
have demonstrated lower restenosis rates in patients treated
with sirolimus eluting stents when compared to bare metal
stents, resulting in fewer repeat procedures. A sirolimus-eluting
coronary stent is marketed by Cordis, a division of Johnson
& Johnson, under the tradename Cypher.[5]
It has been proposed, however, that such stents may increase
the risk of vascular thrombosis.[6]

Additionally
sirolimus is currently being assessed as a theraputic
option for autosomal dominant polycystic kidney disease
(ADPKD). Case reports indicate that sirolimus can reduce
kidney volume and delay the loss of renal function in
patients with ADPKD.[7]

Tuberous
sclerosis complex

Sirolimus
also shows promise in treating tuberous sclerosis complex
(TSC), a congenital disorder that leaves sufferers prone
to benign tumor growth in the brain, heart, kidneys, skin
and other organs. After several studies conclusively linked
mTOR inhibitors to remission in TSC tumors -- specifically
subependymal giant-cell astrocytomas (SEGAs) in children
and angiomyolipomas in adults -- many US doctors began
prescribing sirolimus (Wyeth's Rapamune) and everolimus
(Novartis's RAD001) to TSC patients off-label. Numerous
clinical trials using both rapamycin analogs, involving
both children and adults with TSC, are under way in the
United States.[8]

Most
studies thus far have noted that tumors often regrew when
treatment stopped. Anecdotal reports that the drug ameliorates
TSC symptoms such as facial angiofibromas, ADHD, and autism
remain unproven.

Cancer

The
anti-proliferative effects of sirolimus may have a role
in treating cancer. Recently, it was shown that sirolimus
inhibited the progression of dermal Kaposi's sarcoma in
patients with renal transplants. Other mTOR inhibitors
such as temsirolimus (CCI-779) or everolimus (RAD001)
are being tested for use in cancers such as glioblastoma
multiforme and mantle cell lymphoma.

Combination
therapy of doxorubicin and sirolimus has been shown to
drive AKT-positive lymphomas into remission in mice. Akt
signalling promotes cell survival in Akt-positive lymphomas
and acts to prevent the cytotoxic effects of chemotherapy
drugs like doxorubicin or cyclophosphamide. Sirolimus
blocks Akt signalling and the cells lose their resistance
to the chemotherapy. Bcl-2-positive lymphomas were completely
resistant to the therapy; nor are eIF4E expressing lymphomas
sensitive to sirolimus.[9]
Rapamycin showed no effect on its own.[10][11][12]

As
with all immunosuppressive medications, rapamycin decreases
the body's inherent anti-cancer activity and allows some
cancers which would have been naturally destroyed to proliferate.
Patients on immunosuppressive medications have a 10- to
100-fold increased risk of cancer compared to the general
population. Furthermore, people who currently have or
have already been treated for cancer have a higher rate
of tumor progression and recurrence than patients with
an intact immune system

Potential
treatment for autism

In
a study of sirolimus as a treatment for TSC, researchers
observed a major improvement regarding retardation related
to autism. The researchers discovered sirolimus regulates
one of the same proteins that the TSC gene does, but in
different parts of the body. They decided to treat mice
three to six months old (adulthood in mice lifespans);
this increased the autistic mice's intellect to about
that of normal mice in as little as three days.[13]

Biosynthesis

Rapamycin
is a macrocyclic polyketide isolated from Streptomyces
hygroscopicus that has been shown to exhibit antifungal,
antitumor, and immunosuppressant properties.[1]
The biosynthesis of the rapamycin core is accomplished
by a type I polyketide synthase (PKS) in conjunction with
a nonribosomal peptide synthetase (NRPS). The domains
responsible for the biosynthesis of the linear polyketide
of rapamycin are organized into three multienzymes, RapA,
RapB and RapC which contain a total of 14 modules (See
figure 1). The three multienzymes are organized such that
the first four modules of polyketide chain elongation
are in RapA, the following six modules for continued elongation
are in RapB, and the final four modules to complete the
biosynthesis of the linear polyketide are in RapC.[14]
Then the linear polyketide is modified by the NRPS, RapP,
which attaches L-pipecolate to the terminal end of the
polyketide and then cyclizes the molecule yielding the
unbound product, prerapamycin.[15]

The
core macrocycle, prerapamycin is then modified (See figure
3) by an additional five enzymes which lead to the final
product, rapamycin. First the core macrocycle is modified
by RapI, SAM-dependant O-methyltransferase (MTase), which
O-methylates at C39. Next, a carbonyl is installed at
C9 by RapJ, a cytochrome P-450 monooxygenases (P-450).
Then, RapM, another MTase, O-methylates at C16. Finally,
RapN, another P-450 installs a hydroxyl at C27 immediately
followed by O-methylation by Rap Q, a distinct MTase,
at C27 to yield rapamycin.[16]

The biosynthetic genes responsible for rapamycin synthesis
have been identified. As expected, three extremely large
open reading frames (OFRs) designated as rapA,
rapB and rapC encode for three extremely
large and complex multienzymes, RapA, RapB, and RapC respectively.[14]
The gene rapL has been established to code for
a NAD+ dependant lysine cycloamidase which converts L-lysine
to L-pipecolic acid (See figure 4) for incorporation at
the end of the polyketide.[17]
A gene rapP, which is embedded between the PKS
genes and translationally coupled to rapC encodes
for an additional enzyme, a NPRS responsible for incorporating
L-pipecolic acid, chain termination and cyclization of
prerapamycin. Additionally genes rapI, rapJ,
rapM, rapN, rapO, and rapQ
have been identified as coding for "tailoring" enzymes
which modify the marcrcyclic core to give rapamycin (See
figure 3). Finally, rapG and rapH have been
identified to code for enzymes which have a positive regulatory
role in the preparation of rapamycin through the control
of rapamycin PKS gene expression.[18]

Biosynthesis
of this 31-membered macrocycle begins as the loading domain
is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic
acid, which is derived form the shikimate pathway.[14]
Interestingly, the cyclohexane ring of the starting unit
is reduced during the transfer to module 1. The staring
unit is then modified by a series of Claisen condensations
with malonyl or methylmalonyl substrates which are attached
to an acyl carrier protein (ACP) and extend the polyketide
by two carbons each. After each successive condensation,
the growing polyketide is further modified according to
enzymatic domains which are present to reduce and dehydrate
the polyketide thereby introducing the diversity of functionalities
observed in rapamycin (See figure 1). Once the linear
polyketide is complete, L-pipecolic acid which is synthesized
by a lysine cycloamidase from an L-lysine is added to
the terminal end of the polyketide by an NRPS. Then the
NSPS cyclizes the polyketide giving prerarpmycin, the
first enzyme free product. The macrocyclic core is then
customized by a series of post-PKS enzymes through methylations
by MTases and oxidations by P-450s to yield rapamycin.

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